tbuckley/cabot-search huggingface dataset:
Abstract 395: Resistance to tyrosine kinase inhibitor confers an immunosuppressive microenvironment and cross-resistance to immunotherapy through AXL/PDPK1 axis in liver cancer
Authors: Yunong Xie, Bosheng Huang, Huajian Yu, Jia-Jian Loh, Rainbow Wing-Hei Leung, Terence Lee, Stephanie Ma, Man Tong
Journal: Cancer Research (2023)

Abstract Systemic therapy is the current standard of care for unresectable advanced hepatocellular carcinoma (HCC), the most malignant form of liver cancer. Clinical practice guideline for HCC includes the management of the second-line immunotherapies after patients become unresponsive to first-line targeted therapies using tyrosine kinase inhibitors (TKI), which is expected to generate optimal therapeutic effect due to the distinct mechanism of action between TKIs and immunotherapies. However, evidence from clinical trials suggests that the response to immunotherapy following TKI treatment is often compromised in TKI-resistant HCC as compared with treatment-naïve HCC, indicating a potential cross-resistance to immunotherapy, which impedes the optimal therapeutic effect of the second-line immunotherapies. In the present study, we first explored the therapeutic effect of anti-PD-1 immunotherapy in TKI-resistant HCC and successfully validated the putative cross-resistance to immunotherapy after TKI treatment. We further observed that TKI-resistant HCC exhibits an immune-evasive microenvironment, characterized by decreased CD8+ T cell and dendritic cell infiltration. This is potentially caused by the intratumoral activation of receptor tyrosine kinase AXL and its downstream target PDPK1 which protect TKI-resistant HCC cells from mitochondrial oxidative stress and the cytosolic leakage of mitochondrial DNA, which subsequently suppresses cGAS-STING together with its downstream interferon pathways and immunogenic cell death. Genetic manipulation of AXL and PDPK1 in TKI-resistant HCC cells abrogated the protective effect and thus activated the immunogenic responses. Blockade of AXL with a selective inhibitor BGB324 re-sensitized TKI-resistant HCC to anti-PD-1 treatment. The current findings suggest that targeting AXL/PDPK1 signaling axis might overcome cross-resistance to second-line immunotherapy for HCC patients who progress on TKI treatment. Citation Format: Yunong Xie, Bosheng Huang, Huajian Yu, Jia-Jian Loh, Rainbow Wing-Hei Leung, Terence Lee, Stephanie Ma, Man Tong. Resistance to tyrosine kinase inhibitor confers an immunosuppressive microenvironment and cross-resistance to immunotherapy through AXL/PDPK1 axis in liver cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 395.
Abstract 5348: Targeting MEK, alone and in combination with BRAF, in metastatic BRAFK601E-mutated melanoma
Authors: Sze Man Chan, Sin Ting Chow, Sai Fung Yeung, Kwok Wing Stephen Tsui
Journal: Cancer Research (2023)

Abstract Mitogen-activated protein kinase/ERK signaling pathway has been one of the major mechanisms underlying melanoma haboring BRAF mutation. Of these, K601E mutation belongs to a rare mutation sub-type, comprising only 3% of the BRAF mutations in melanoma. Although patients with BRAF V600E/K mutation respond to MEK inhibitor, whether it also applies to those with BRAF K601E mutation remains elusive. Here, we examined the effects of MEK and BRAF/MEK inhibition on BRAFK601E-expressing melanoma cells. Melanoma cell line (MeWo) was transfected with doxycycline-inducible vector encoding wild-type or K601E-mutant BRAF. Subsequently, cells or xenograft-bearing mice were treated with trametinib, dabrafenib plus trametinib or sorafenib plus trametinib. Compared with BRAFWT, MTT assay demonstrated that BRAFK601E cells were more sensitive towards drug treatment. The effects of combined treatment were more profound. Tumorigenicity assay showed that trametinib treatment inhibited tumor growth of BRAFK601E xenografts. Our preliminary results demonstrated the therapeutic values of MEK and BRAF/MEK inhibitors against BRAFK601E-mutated melanoma. As previous studies report the superior therapeutic effects of BRAF/MEK inhibitors over MEK inhibitor alone, phenotype characterization of the cells, as well as underlying mechanisms behind such response, worth further investigation. Citation Format: Sze Man Chan, Sin Ting Chow, Sai Fung Yeung, Kwok Wing Stephen Tsui. Targeting MEK, alone and in combination with BRAF, in metastatic BRAFK601E-mutated melanoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5348.
Abstract 970: Clinical analysis of patients (pts) with lung cancer treated with anti-PD1/PDL1 therapy
Authors: Xin Zhao, Siyao Liu, Junyan Su
Journal: Cancer Research (2023)

Abstract Background: Characterization of Lung cancer treated with anti-PD1/PDL1 therapy was approach to predict the clinical benefit. This research is a prospective and observational study of long-term immunization therapy safety in routine clinical practice in lung cancer. Methods: This study obtained 395 Chinese patients lung cancer patients who underwent surgical resection or biopsies from January 2020 to January 2022. It is aimed to evaluated the value of TMB, MSI, and PD-1 expression in the pts subset that was therapy at anti-PD1/PDL1 therapy(n=47), other anticancer therapies (n=348) included chemoradiation therapy(55%), docetaxel(18%), EGFR-TKIs (16%), pemetrexed (5%) etc. Results: In this cohort, lung cancer pts treated with anti-PD1/PDL1 therapy had a higher proportion of MSI-H than others (7.7% vs 3.4%). PD-L1 High expression in two groups (anti-PD1/PDL1 therapy vs others) about in 19.1%(n=9) vs 10.6% (n=37), and low expression in 8.9% (n =31) vs 10.6% (n=5) pts. Median TMB was 13 mut/Mb from anti-PD1/PDL1 therapy and 9.6 mut/Mb from other therapy. Conclusions: Lung cancer pts were integrated after to immunotherapy vs other therapy, most pts received multiple subsequent anticancer therapies. In this study, immune-related biomarker analysis of lung cancer populations with multiple treatment methods may help improve the efficacy of precise treatment in lung cancer. Table Other therapy(n = 348) Anti-PD1/PDL1 therapy(n = 47) PD-L1 IHC High 10.6% 19.1% PD-L1 IHC Low 8.9% 10.6% TMB Median (mut/Mb) 9.6 13.0 MSS Status 76.0% 74.4% MSI Low Status 20.7% 17.9% MSI High Status 3.4% 7.7% Citation Format: Xin Zhao, Siyao Liu, Junyan Su. Clinical analysis of patients (pts) with lung cancer treated with anti-PD1/PDL1 therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 970.
Abstract 969: Non-invasive detection of plasma proteins in immune checkpoint inhibitor-treated patients with advanced non-small cell lung cancer
Authors: Simone Stensgaard, Astrid Thomsen, Julie G. Dissing, Sofie Helstrup, Peter Meldgaard, Boe S. Sorensen
Journal: Cancer Research (2023)

Abstract Introduction: Immunotherapy has altered the therapeutic landscape for patients with advanced non-small cell lung cancer (NSCLC). The immune checkpoint inhibitor pembrolizumab targets the PD-1 signaling axis and has produced durable clinical response, but the efficacy is dependent on the anti-tumor activity of the immune system. We aimed to identify plasma proteins that could be used to identify patients who will respond to treatment with pembrolizumab. Methods: Plasma samples were collected from 42 patients with advanced NSCLC before start of treatment with pembrolizumab and after 1 and 2 cycles of treatment. The plasma samples were analyzed using the Olink Proximity Extension Assay with an immuno-oncology panel detecting the expression level of 92 circulating plasma proteins. To evaluate the association between plasma protein expression and progression-free survival (PFS) the patients were stratified into two subgroups based on the median PFS (median=220 days). Results: The patient subgroup with long PFS had significantly higher levels of Fas Ligand (FasL) and Inducible T Cell Costimulator Ligand (ICOSLG) before the start of treatment than patients with short PFS (p=0.0021 and p=0.0230 for FasL and ICOSLG). FasL remained significantly higher for patients with long PFS after 1 and 2 cycles of treatment (p=0.0170 and p=0.0190, respectively). Kaplan-Meier analysis of baseline ICOSLG and FasL expression showed longer PFS and overall survival (OS) for patients with high ICOSLG expression (p=0.0489 and p=0.0223 for PFS and OS) and for patients with high FasL expression (p=0.0064 and p=0.0069 for PFS and OS). An association was found between ICOSLG and FasL expression at baseline (R2=0.1403, p=0.0145), however the two proteins showed different dynamics during treatment, with FasL expression increasing during the early weeks of treatment, while little to no change is observed in ICOSLG expression. Combining the baseline expression of the two proteins identified a patient group with either a high expression of FasL or ICOSLG, or both, that had superior PFS (p=0.044) and OS (p=0.0017). Conclusion: These findings suggest that the expression of FasL and ICOSLG at baseline may help identify patients who will respond to treatment with pembrolizumab. Citation Format: Simone Stensgaard, Astrid Thomsen, Julie G. Dissing, Sofie Helstrup, Peter Meldgaard, Boe S. Sorensen. Non-invasive detection of plasma proteins in immune checkpoint inhibitor-treated patients with advanced non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 969.
Abstract 4035: Preclinical activity of BAY 2927088 in HER2 mutant non-small cell lung cancer
Authors: Franziska Siegel, Gizem Karsli-Uzunbas, Kristyna Kotynkova, Quinn McVeigh, Stephan Siegel, Daniel Korr, Volker Schulze, Markus Berger, Georg Beckmann, Andrew Cherniack, Matthew Meyerson, Heidi Greulich
Journal: Cancer Research (2023)

Abstract HER2 mutations are potent oncogenic drivers in various cancer indications. In NSCLC, about 2% of patients carry either a HER2 exon20 insertion mutation or a HER2 point mutation. With the recent approval of fam-trastuzumab deruxtecan-nxki, the first targeted treatment option became available for HER2 mutant NSCLC patients. However, there remains a high unmet need for more effective and better tolerated therapies with the potential to improve response rates and response durability. BAY 2927088 is a reversible small molecule inhibitor that is currently being evaluated in a first-in-human, phase I clinical trial in patients with EGFR mutant NSCLC (NCT05099172). Here, we present the preclinical activity profile of BAY 2927088 in HER2 mutant NSCLC. BAY 2927088 shows strong antiproliferative activity in an isogenic Ba/F3 cell line panel of HER2 exon20 insertion mutations as well as HER2 point mutations. BAY 2927088 is highly potent on the most frequent HER2 exon20 insertion mutations A775insYVMA and G776del insVC, as well as in the HER2 point mutations S310F, S335C, and L755S, among others. In addition, the compound was active in a subset of endogenously HER2 mutant cancer cell lines. The in vitro activity of BAY 2927088 was validated in vivo in a patient-derived xenograft model carrying the HER2 exon20 insertion mutation A775insYVMA. The strong preclinical activity of BAY 2927088 in HER2 mutant NSCLC supports clinical evaluation in this indication and might offer a novel targeted therapy option for NSCLC patients that carry HER2 mutations. Citation Format: Franziska Siegel, Gizem Karsli-Uzunbas, Kristyna Kotynkova, Quinn McVeigh, Stephan Siegel, Daniel Korr, Volker Schulze, Markus Berger, Georg Beckmann, Andrew Cherniack, Matthew Meyerson, Heidi Greulich. Preclinical activity of BAY 2927088 in HER2 mutant non-small cell lung cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4035.
Abstract 3756: miR-145 and its gene targets as therapeutic target and prognostic biomarkers for non-small cell lung cancer
Authors: William C. Cho, Chi F. Wong, Leo K. Li, Alvin H. Fong
Journal: Cancer Research (2023)

Abstract Introduction: Our previous study found that miR-145 was downregulated in non-small cell lung cancer (NSCLC) tissues and it could inhibit cell proliferation in transfected NSCLC cells. This study aimed to investigate the potential anticancer effect and tumor suppressive function of miR-145, to identify its gene targets, as well as to assess the role of its gene targets as prognostic biomarkers for NSCLC patients. Materials and Methods: Cell proliferation, transwell migration, and invasion assays were performed on three miR-145 mimics transfected NSCLC cells. The effect of miR-145 in the cell cycle in vitro was assessed by flow cytometry analysis. In vivo transfection of miR-145 was performed to examine the cancer growth in eight BALB/c nude mice. Luciferase reporter assay was used to identify the gene targets. To reveal the role of the identified gene targets in patient survival, the clinical data of 500 lung adenocarcinoma patients from The Cancer Genome Atlas (TCGA) database was used for Kaplan-Meier survival analysis. Results: Upregulation of miR-145 significantly inhibited proliferation, migration, and invasion in NSCLC cells in vitro. Flow cytometry analysis revealed that the transfection of miR-145 into NSCLC cells did not show any effect in the cell cycle. After 37 days, transfection of miR-145 showed a reduction in tumor size (49% smaller) and tumor weight (57% lighter) than mimic negative in vivo. MicroRNA target prediction database miRTarBase and luciferase reporter assays identified GOLM1 and RTKN as the direct targets of miR-145. TCGA survival analysis found that the high expressions of GOLM1 (p &amp;lt; 0.0001) and RTKN (p &amp;lt; 0.0045) were significantly correlated with poor overall survival in lung adenocarcinoma patients. Conclusion: Our results revealed that miR-145 inhibited proliferation, migration, and invasion, but did not affect cell cycle regulation in NSCLC. It also caused a reduction in tumor growth and weight. Most importantly, we identified two direct targets (GOLM1 and RTKN) of miR-145, in which RTKN was first identified as a miR-145 target in NSCLC. Moreover, both GOLM1 and RTKN play an imperative role in patients’ overall survival. Taken together, our findings suggest that miR-145 may serve as a molecular therapeutic target for NSCLC, and its gene targets GOLM1 and RTKN may serve as prognostic biomarkers. Their potential clinical applications warrant further investigation. Citation Format: William C. Cho, Chi F. Wong, Leo K. Li, Alvin H. Fong. miR-145 and its gene targets as therapeutic target and prognostic biomarkers for non-small cell lung cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3756.
Abstract 2701: pH-responsive targeted-nanoparticle releases encapsulated ERK-inhibitor effectively in the hypoxic microenvironment and sensitizes gemcitabine in pancreatic cancer cells
Authors: Debasmita Dutta, Archana De, Raj Shankar Hazra, Pratyusha Ghosh, Mohiuddin Quadir, Snigdha Banerjee, Sushanta K. Banerjee
Journal: Cancer Research (2023)

Abstract Therapeutic strategies for Pancreatic ductal adenocarcinoma (PDAC), one of the deadliest types of aggressive malignancies, remain challenging with poor prognosis, high mutational rate, and lowest patient survival among other cancers. The treatment options for managing PDAC are limited to surgery, radiation, and chemotherapy. However, surgery is the only treatment option that can cure the disease in about twenty percent of cases. Thus, Gemcitabine (GEM) remains the first-line drug in the clinic for PDAC treatment despite suboptimal clinical effects. These are primarily due to weak drug delivery and the development of chemoresistance resulting from mutant-K-RAS/AKT/ERK signaling-mediated desmoplastic cages. Several new therapeutic approaches, including nanoparticle-based drug delivery procedures, are currently being investigated. In this study, we designed a pH-responsive PEG-b-poly (carbonate) block copolymer encapsulated ERK inhibitor (SCH772984) nanoparticles surface functionalized with tumor-penetrating peptide, iRGD to specifically target PDAC tumor tissue. By utilizing the ERKi-encapsulated pH-responsive targeted nanoparticles, we performed a combinational drug treatment of GEM and ERKi. We found that the pH-responsive targeted nanocarrier efficiently released ERKi in the hypoxic environment. The free GEM, combined with nanoencapsulated ERKi, demonstrated significant synergistic outcomes in vitro colony forming ability, migration, and motility in pancreatic cancer cell line MiaPaCa2. Moreover, combination therapy significantly enhanced the GEM effect in reducing PDAC growth in KPC mice and increasing the survival of the mice. Thus, our studies indicate that pH-responsive targeted nanocarrier-based delivery of ERKi in the hypoxic area of PDAC enhances the efficacy of GEM in PDAC. Citation Format: Debasmita Dutta, Archana De, Raj Shankar Hazra, Pratyusha Ghosh, Mohiuddin Quadir, Snigdha Banerjee, Sushanta K. Banerjee. pH-responsive targeted-nanoparticle releases encapsulated ERK-inhibitor effectively in the hypoxic microenvironment and sensitizes gemcitabine in pancreatic cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2701.
Abstract 4997: PLK1 promotes the metastasis and drug resistance in melanoma
Authors: Fengyi Mao, Yifan Kong, Chaohao Li, Yanquan Zhang, Xiongjian Rao, Qiongsi Zhang, Xinyi Wang, Zhiguo Li, Xiaoqi Liu
Journal: Cancer Research (2023)

Abstract Melanoma is one of the most frequently diagnosed cancers in the caucasian population of both genders. The survival rate of advanced melanoma patients will be exceedingly poor, as low as 27.3%. BRAF-V600E is the most common mutation found clinically, resulting in the constitutive activation of the MAPK signaling pathway. Vemurafenib, a specific inhibitor of mutant BRAF, has shown an impressive response in phase 3 clinical trials and was approved by FDA in 2011. However, due to the rapid development of resistance, the duration of response under a single treatment is frequently short, highlighting the urgent requirement for novel therapy in melanoma treatment. Polo-like kinase 1 (PLK1), a crucial cell cycle regulator, participates in multiple mitotic processes, including centrosome maturation, mitotic entry, spindle assembly, sister chromatid segregation, mitotic exit, and cytokinesis. Compared to normal tissues, the expression level of PLK1 significantly upregulates in multiple cancers. More importantly, the expression level of PLK1 negatively correlates with the melanoma patients’ survival rate based on the TCGA database. Besides, PLK1 is identified as an oncogene to promote proliferation, motility, and resistance to various drugs. In the present study, we found that overexpression of PLK1 promotes tumor growth, metastasis, metabolic reprogramming, and vemurafenib resistance in the BrafCA/Ptenloxp mouse melanoma model. Through phosphorylation, overexpressed PLK1 stabilizes BACH1, a critical transcriptional factor of multiple metastatic and metabolic genes, and protects it from degradation. Subsequently, a higher level of BACH1 leads to increasing metastasis, upregulation of glycolysis, and suppression of OXPHOs. Besides, we have validated the strong synergy between PLK1 inhibitor volasertib and vemurafenib in treating melanoma carrying BRAF-V600E. Our in vitro and in vivo experiments have shown an improved efficacy of this combined therapy on inhibition of cell proliferation, induction of cell death, and suppression of cell metastasis compared to mono-treatment. In short, our data has indicated PLK1 as a potent and promising target in cancer treatment. Citation Format: Fengyi Mao, Yifan Kong, Chaohao Li, Yanquan Zhang, Xiongjian Rao, Qiongsi Zhang, Xinyi Wang, Zhiguo Li, Xiaoqi Liu. PLK1 promotes the metastasis and drug resistance in melanoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4997.
Abstract 1819: Integrin inhibitor GLPG-0187 promotes T-cell killing of mismatch repair-deficient colorectal cancer cells by suppression of SMAD/TGF-β signaling
Authors: Brooke Verschleiser, William MacDonald, Lindsey Carlsen, Kelsey E. Huntington, Lanlan Zhou, Wafik El-Deiry
Journal: Cancer Research (2023)

Abstract Colorectal cancer is the third leading cause of cancer-related death and the third most common cause of cancer. As the five-year survival with advanced metastatic colorectal cancer (mCRC) is 14%, new treatment strategies are needed. Immune checkpoint blockade which takes advantage of an individual's immune system in order to fight cancer, is a promising future direction of research, although it is only effective and approved for the treatment of mismatch repair (MMR)-deficient CRCs. Long-term outcomes even in MMR-deficient mCRC suggest that most patients are not cured but eventually develop therapy resistance. We hypothesized that targeting TGF- β signaling may enhance immune-mediated T-cell killing by MMR-deficient CRC cells. Using GLPG-0187, an inhibitor of multiple integrin receptors and TGF- β, we demonstrate minimal cytotoxicity against MMR-deficient HCT116 or p53-null HCT116 human CRC cells. However, GLPG-0187 promoted significant immune cell killing of the CRC cells by TALL-104 T lymphoblast cells. GLPG-0187 reduced pSMAD2 in HCT116 p53-null cells either in the absence or presence of exogenous TGF- β. We observed a reduction in CCL20, CXCL5, prolactin, and TRAIL-R3 while GDF-15 was increased in TALL-104 cells treated with a T-cell activating dose of GLPG-0187 (4 μM). Our results suggest that TGF- signaling inhibition by a general integrin receptor inhibitor may boost T-cell killing of MMR-deficient colorectal cancer cells, and suggest that a combination of anti-GDF-15 in combination with TGF- β blockade should be further investigated in the treatment of MMR-deficient mCRC. Our results support the development of a novel immune-based therapeutic strategy to treat colorectal cancer by targeting the TGF-β signaling pathway through integrin receptor blockade. Citation Format: Brooke Verschleiser, William MacDonald, Lindsey Carlsen, Kelsey E. Huntington, Lanlan Zhou, Wafik El-Deiry. Integrin inhibitor GLPG-0187 promotes T-cell killing of mismatch repair-deficient colorectal cancer cells by suppression of SMAD/TGF-β signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1819.